Phase I, First in Human, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of X-82 in Patients With Advanced Solid Tumors
- Histologically or cytologically confirmed diagnosis of advanced solid tumor
malignancy that is not responsive to standard therapies or for which there is no
- Eastern Cooperative Group (ECOG) Performance Status score of 0 or 1.
- Life expectancy of at least 12 weeks.
- Ability to swallow and retain oral medication.
- Adequate organ system function, defined as follows:
- Absolute neutrophil count (ANC) ≥1.5 x 109/L
- Platelets ≥100 x 109/L
- Hemoglobin ≥9 g/dL
- Total bilirubin ≤1.5 times the upper limit of normal (ULN)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x the
upper limit of normal (ULN) if no liver involvement or ≤5 x the upper limit of
normal with liver involvement.
- Creatinine ≤ 1.5 x ULN, OR calculated creatinine clearance ≥ 50 mL/min as
calculated by the Cockcroft-Gault method, OR 24-hour measured urine creatinine
clearance ≥ 50 mL/min.
- Male patients willing to use adequate contraceptive measures.
- Female patients who are not of child-bearing potential, and female patients of
child-bearing potential who agree to use adequate contraceptive measures and who have
a negative serum or urine pregnancy test within 24 hours prior to initial trial
- Patients must have measurable or evaluable disease.
- Patients must be ≥ 18 years of age.
- Patients entering this study must be willing to provide tissue from a previous tumor
biopsy (if available) for correlative testing. If tissue is not available, a patient
will still be eligible for enrollment into the study.
- Willingness and ability to comply with trial and follow-up procedures.
- Ability to understand the nature of this trial and give written informed consent.
- Patients currently receiving cancer therapy (i.e., chemotherapy, radiation therapy,
immunotherapy, biologic therapy, hormonal therapy [with the exception of LHRH
agonists for prostate cancer], surgery and/or tumor embolization).
- Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter)
prior to the first dose of X-82. A minimum of 10 days between termination of the
investigational drug and administration of X-82 is required. In addition, any
drug-related toxicity should have recovered to grade 1 or less.
- Any major surgery, radiotherapy, or immunotherapy within the last 21 days (limited
palliative radiation is allowed ≥2 weeks). Chemotherapy regimens with delayed
toxicity within the last 4 weeks (or within the last 6 weeks for prior nitrosourea or
mitomycin C). Chemotherapy regimens given continuously or on a weekly basis with
limited potential for delayed toxicity within the last 2 weeks.
- Patients with a known allergy or delayed hypersensitivity reaction to drugs
chemically related to X-82 (sunitinib, sorafenib or pazopanib) or to the active
ingredient of X-82.
- Concomitant use of drugs with a risk of causing prolonged QTc and/or Torsades de
- Concomitant use of herbal medications (i.e. St. John's wort, Kava, ephedra (ma
huang), ginko biloba) at least 7 days prior to the first dose of study drug and
throughout participation in the trial.
- Patients with known CNS metastases, unless metastases are treated and stable and the
patients do not require systemic steroids
- Treatment with therapeutic doses of coumarin-type anticoagulants (maximum daily dose
of 1mg allowed for port line patency permitted). Low molecular weight heparin (LMWH)
will be allowed.
- Females who are pregnant or breastfeeding.
- Presence of active gastrointestinal (GI) disease or other condition that will
interfere significantly with the absorption, distribution, metabolism, or excretion
- Decreased left ventricular function at study entry defined as LVEF <50% by either
Echocardiogram or MUGA scan.
- Patients who have previously experienced myocardial infarction, severe/unstable
angina, coronary/peripheral arterial bypass, symptomatic congestive heart failure
(New York Heart Association [NYHA] Class 3 or 4), arterial thrombosis,
cerebrovascular accident, or transient ischemia, in the 60 days prior to Day 1 of
- Patients with inadequately controlled hypertension (defined as BP > 150/100) with or
without current antihypertensive medications. Patients with a history of additional
risk factors for Torsades de Pointes (e.g. familial long QT syndrome, heart failure,
left ventricular hypertrophy, slow heart rate (<45 bpm)).
- Patient with a QTc interval ≥450 msecs. or other significant ECG abnormalities as
determined the investigator.
- A serious active infection at the time of treatment, or another serious underlying
medical condition that would impair the ability of the patient to receive protocol
- Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.
- Concurrent condition that in the investigator's opinion would jeopardize compliance
with the protocol
- Inability or unwillingness to comply with study and/or follow-up procedures outlined
in the protocol
- Patients with a history of intolerance to, or significant toxicity with, VEGFR
tyrosine kinase inhibitor(s) (TKI).
- Patients entering the expansion after the determination of MTD are limited to
previous treatment with one anti-VEGFR TKI